Organ transplantation, especially of renal type, has made substantial strides in the past few decades, with the introduction of improved immunosuppressive regimens, organ preservation, and pre- and postoperative care. Nevertheless, there is considerable room for improvement, particularly in terms of improving long-term outcome. Initial ischemia/reperfusion injury occurring secondary to organ retrieval, storage, and transplantation has been associated with subsequent deterioration and transplant failure. In renal transplantation the absence of immediate allograft function is known as delayed graft function (DGF) which is commonly and broadly defined as the need of dialysis during the first week after transplantation. Delayed graft function is the most common allograft complication in the immediate posttransplant period, affecting up to 50% of primary cadaveric renal transplants (Ojo A O et al. Delayed graft function: risk factors and implications for renal alloagraft survival. Transplantation 63, 7:968-974, 1997; Koning O H J et al. Risk factors for delayed graft function in cadaveric kidney transplantation. Transplantation 63, 11:1620-1628, 1997). Although different etiologies may cause DGF of implanted allograft, there is accumulating experimental and clinical evidence suggesting that post-ischemic reperfusion injury to allograft may represent the major key event responsible for the occurrence of DGF. There is unanimous agreement that the combination of DGF and early rejection is a severe indicator of poor graft survival and that the occurrence of DGF leads to an increased risk of acute rejection (Carmellini M et al. Delayed graft function adversely affects one-year graft survival of cadaveric renal transplants. Transplant Proc 28, 1.359-360, 1996). The pathogenesis of ischemia/reperfusion injury is now known to involve cytokines and particularly surface adhesion molecules, the expression of which initiates the attachment of inflammatory cells. Evidence from experimental animals with acute renal ischemia has shown that the intercellular adhesion molecule-1 (ICAM-1) is promptly up-regulated after injury and that neutrophil, T cell, and macrophage infiltrations subsequently occur. Interleukin-8 (IL-8), a cytokine with a potent chemotactic effect for polymorphonuclear cells (PMN), can be generated by the activation of endothelial cells that follows reperfusion and may contribute to the complex events ultimately leading to delayed graft function due to ischemia/reperfusion injury. Recently, new compounds that selectively inhibit the biological activity of IL-8 have been discovered. Among these, R (−)-N-[2-(4-Isobutylphenyl)propionyl]-methanesulfonamide, hereinafter referred to as (R)-ibuprofen methanesulfonamide, and its L-lysine salt (hereinafter referred to as DF 1681B), have been described in international patent application WO 00/24710 as selective in vitro inhibitors of the chemotaxis of neutrophils induced by IL-8 and therefore desirably suitable for the treatment of neutrophil-dependent pathologies.
DF 1681B has now been shown to inhibit chemotaxis in vivo in a mouse model and to inhibit PMN infiltration in different models of ischemia/reperfusion injury in mice and rats.
Indeed, according to the current state of the art, the selective inhibition of IL-8-induced chemotaxis is not a sufficient condition for the protection of a transplanted organ from functional injury. In fact, the scientific literature identifies numerous factors involved in the etiology of the delay in functional recovery of the transplanted kidney, among which factors, IL-8 does not certainly appear as one of the most important: for example, IL-8, together with IL-3 and soluble CD 23, (Kutukculer N. et al., Transplantation, 1995, 59(3), 333-40) is reported to be of no diagnostic use for organ rejection given that, in any case, high levels of these markers were also present in transplant patients who were wholly free from rejection phenomena. Moreover, in addition to IL-3, IL-8 and CD 23, scientific literature identifies various other possible pro-inflammatory molecules as possible pathogenetic factors of the delay in the functional recovery of the transplanted organ, such as, for example, IL-1beta, IL-2, IL-10, IL-17, MIP-1beta, MCP-1, etc. It follows that, from the literature data, an aspecific inhibitor of the inflammatory response or, at the least, of leukocyte recruitment would appear necessary for the inhibition of reperfusion injury in organ transplantation, especially that of kidneys.